Matrix metalloproteinases (MMPs) are a family of structurally related zinc-containing enzymes that have been reported to mediate the breakdown of connective tissue in normal physiological processes such as embryonic development, reproduction, and tissue remodeling. Over-expression of MMPs or an imbalance between MMPs has been suggested as factors in inflammatory, malignant and degenerative disease processes characterized by the breakdown of extracellular matrix or connective tissues. MMPs are, therefore, targets for therapeutic inhibitors in several inflammatory, malignant and degenerative diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation (which leads to restenosis and ischemic heart failure) and tumor metastasis.
The mammalian MMP family has been reported to include at least 20 enzymes (Chem. Rev. 1999, 99, 2735-2776). Collagenase-3 (MMP-13) is among three collagenases that have been identified. Based on identification of domain structures for individual members of the MMP family, it has been determined that the catalytic domain of the MMPs contains two zinc atoms; one of these zinc atoms performs a catalytic function and is coordinated with three histidines contained within the conserved amino acid sequence of the catalytic domain. MMP-13 is over-expressed in rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, breast carcinoma, squamous cell carcinomas of the head and neck, and vulvar squamous cell carcinoma. The principal substrates of MMP-13 are fibrillar collagens (types I, II, III) and gelatins, proteoglycans, cytokines and other components of ECM (extracellular matrix).
Matrix metalloproteinase inhibitors have been tested clinically in a few indications. Most predominantly in arthritis and cancer. Inhibitors that have entered clinical trials for an oncologic indication include prinomastat (AG3340; Agouron/Pfizer), BAY 12-9566 (Bayer Corp.), batimistat (BB-94; British Biotech, Ltd), BMS-275291 (formerly D2163; Celltech/Bristol-Myers Squibb), marimastat (BB 2516; British Biotech, Ltd./Schering-Plough) and MMI270(B) (formerly CGS-27023A; Novartis). Many of the hydroxamic acid containing MMP inhibitors exhibit very broad toxicities in humans. For example, Marimastat, which contains a hydroxamate moiety, exhibited time-dependent and dose-dependent musculoskeletal toxicities (arthralgia, myalgia, tendinitis) in humans. Other toxicities for marimastat include ascites, disseminated carcinoma, chills, cholangitis, dizziness, dyspnea, edema, fatigue, fever, gastrointestinal (anorexia, nausea, vomiting, diarrhea, constipation), gastrointestinal hemorrhage, headache, heartburn, hepatic toxicity, hypercalcemia, hyperglycemia, rash, and shortness of breath. It is not known whether the toxicities exhibited by many of the MMP inhibitors are attributed to the hydroxamic acid moiety, however, it is clear that having an MMP inhibitor that does not contain a hydroxamic acid group or bind zinc could reduce many potential metabolic liabilities. One of the few non-hydroxamic acid containing compounds that binds allostericically to MMP-13 and does not bind zinc are a series of bis-amide pyrimidine compounds disclosed in WO 02/064571, WO 03/049738, WO 04/041788 and WO 04/060883. All of the bis-amide pyrimidines represented in WO 02/064571, WO 03/049738, WO 04/041788 and WO 04/060883 form the bis-amide attachments via two primary benzylic amines having no carbon substitution on the benzylic carbon atoms. WO 07/079199 discloses that substitution of one of the benzylic hydrogens on at least one of the benzyl carbons forming the bis-amide pyrimidines with a methyl group results in an enhancement of the microsomal stability in Rat and/or Human microsomes. This implies that there may be some cytochrome P450 induced transformation that may be occurring at the benzylic carbon. One possible transformation is the P450 induced oxidative dealkylation of the benzylic carbon to give a resulting benzaldehyde (Illey, J.; Tolando, R.; Constantino, L. J. Chem. Soc., Perkin Trans. 2, 1299-1305, (2001)). One consequence of placing a methyl group on the benzylic position is that it transforms the achiral compound (i.e., a molecule that has a plane of symmetry) into a molecule that is chiral (i.e., a molecule that has a non-superposable mirror image) having both an R- and S-configuration. WO 07/079199 also discloses that the spatial orientation of the substituted methyl group can have a profound effect on the inhibitory activity of the molecule. WO07/079199 discloses that positioning the substituted methyl group in the “R” configuration produces a molecule that is much less potent than the same molecule with the methyl group positioned in the “S” configuration. In some cases differences in IC50 are observed of more than a factor of ten when the chirality of the substituted methyl group changes from an “R” to an “S” configuration. Engel & Co-workers (Engel, C. K. et al. Chemistry & Biology, Vol. 12, 181-189, (2005)) disclose the x-ray crystal structure of three separate symmetrical bis-amide pyrimidine MMP-13 inhibitors and show that they bind to an allosteric site known as the S1′ side pocket. Clearly, the methyl group in the benzylic position with the less active, “R” configuration must be interacting negatively within this S1′ side pocket. In fact, x-ray and molecular modelling analysis of a bis-amide pyrimidine inhibitor within the S1′ side pocket of MMP-13 by Pirard (Pirard, B.; Drug Discovery Today, 12, No. 15/16, (2007)) shows very little extra space around the benzylic carbon. The result of having to synthesize a molecule with a methyl or other alkyl group oriented in the more active “S” enantiomeric configuration is that a much longer & laborious synthetic scheme must be devised and executed. Another problem with turning the bis-amide pyrimidine into a chiral molecule is that now one has the added problem of the possibility that the chiral center might racemize while the compound is in storage and/or when administered in-vivo. It would be of benefit if one could reduce the level of microsomal instability that is observed at the benzylic carbon position without resulting in the creation of a chiral molecule. One possible answer is to replace the hydrogens from one or both benzylic carbons with deuterium atoms and hence avoid creating a chiral center. Such deuterium substitution could inhibit P450 induced transformations at the benzylic carbon while still maintaining the molecule's potency for inhibiting MMP-13.
Kushner and coworkers (Kushner, D. J.; Baker, A.; Dunstall, T. G. Can J. Physiol Pharmacol, 77(2), (1999) p. 79-88) have presented examples of how incorporating deuterium into a drug can often reduce the level of metabolic induced transformations especially those mediated by Cytochrome P450. This reduce rate of Cytochrome P450 induce metabolism can sometimes translate directly to enhanced bioavailability. The reason for this is due to the fact that atomic substitution of a hydrogen by a deuterium in a drug alters the strength of the carbon-deuterium bond of the drug, while keeping it's 3D surface very similar to that of the nondeuterated version. Substitution of deuterium for hydrogen, can give rise to an isotope effect that can alter the pharmacokinetics of the drug. In a reaction in which the cleavage of a C—H bond is rate determining the same reaction of the C-D analogue will be reduced. For example Schneider and coworkers (Scheneider, F.; et al., BiRDS Pharma GmbH, Arzneimittel Forschung (2006), 56(4), p. 295-300) have shown that replacing several of the hydrogen atoms around one of the aromatic rings of the COX-2 inhibitor Refecoxib (4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one) with deuterium (at positions 2′,3′,4′,5′ an 6′) enhanced the microsomal stability and oral bioavailability of the drug without affecting it's COX-2 selectivity. If one applied this strategy to one or more of the benzyl positions of the bis-amide pyrimidine one could reduce its susceptibility to cytochrome P-450 hydroxylation and ultimately enhance its overall bioavailability and possibly it's target tissue compound concentration.
Another possible affect of incorporating deuterium into a drug is on its polymorphic (i.e., different crystalline forms) properties. For example, Hirota and Urushibara (Bulletin of the Chemical Society of Japan, 32(7), (1959), 703-706) have shown that replacing a single vinylic hydrogen for deuterium on Allocinnamic acid can change both the melting point and the intensity of the x-ray diffraction pattern of the molecule. Lin and Guillory (Journal of Pharmaceutical Science, Vol. 59(7), (2006), 972-979) have shown that sulfanilamide-d4 exhibited smaller heats of transition and heats of fusion for its various crystalline states as compared to it's corresponding non-deuterated forms. Finally, Crawford and co-workers (Crawford, S. et al., Angewandte Chemie International Edition, 48(4), (2009), 755-757) recently showed that the crystalline form of fully deuterated pyridine adopts a unique configuration that can only be obtained under high pressure with the non-deuterated parent. Their work clearly showed that replacing hydrogen for deuterium changes the strength of interaction between various atoms in neighboring molecules causing a change in the crystalline arrangement to one that is more energetically favorable. This change in crystalline arrangement or polymorph may allow for improved dissolution properties and enhanced bioavailability.
This invention discloses MMP inhibitors and specifically inhibitors of MMP-13 with surprising and unexpected improvements in their properties when bearing two or more deuterium atoms at positions R1, R2, R3 and/or R4 in the compounds of Formula (I) and (II). The unexpected advantages observed for the deuterium substituted compounds of this invention include improvements in microsomal stability, pharmacokinetics (PK), cell viability and/or enhanced dissolution characteristics. It is believed that these new findings and the specific structural modifications which this invention discloses will lead to inhibitors of MMP-13 with improved pharmaceutical value.